Nuclear magnetic resonance(NMR)spectroscopy is an indispensable tool to probe weak protein-ligand interactions,which are key to the hit identification and hit-to-lead evolution in fragment-based drug discovery(FBDD).T...Nuclear magnetic resonance(NMR)spectroscopy is an indispensable tool to probe weak protein-ligand interactions,which are key to the hit identification and hit-to-lead evolution in fragment-based drug discovery(FBDD).The integration of NMR technology in FBDD has facilitated the development of a diverse array of candidate compounds and FDAapproved drugs.Here,we summarized the rapid advancement and application of NMR techniques in contemporary China,which serves as a catalyst for the ongoing prosperousness of fragment-derived inhibitors against various targets.展开更多
Fragment-based drug discovery （FBDD） has been widely applied in the research of aspartyl protease inhibitors. In the present study, we reported our work on 2-aminobenzimidazole as the original fragment, which was pr...Fragment-based drug discovery （FBDD） has been widely applied in the research of aspartyl protease inhibitors. In the present study, we reported our work on 2-aminobenzimidazole as the original fragment, which was predicted to bind with the catalytic aspartyl dyad （Asp228 and Asp32） of D-site amyloid precursor protein cleaving enzyme 1 （BACE1）. A series of novel 2-aminobenzimidazole derivatives were designed and synthesized. The results from FRET assay revealed that three out of the 12 designed 2-aminobenzimidazoles could inhibit more than 50% of the enzymatic potency of BACE1 at 10 pM. Docking study showed that 2-aminobenzimidazole could form multiple hydrogen bonds and occupy S1/$2＇ pockets well.展开更多
基于片段的药物设计(Fragment-Based Drug Design,FBDD)是药物研发的主流方法之一。如何高效从海量药物大数据中筛选出具有相似分子片段的药物小分子成为生物化学研究领域的挑战性问题。针对目前人工筛选耗时长、效率低、药物筛选周期...基于片段的药物设计(Fragment-Based Drug Design,FBDD)是药物研发的主流方法之一。如何高效从海量药物大数据中筛选出具有相似分子片段的药物小分子成为生物化学研究领域的挑战性问题。针对目前人工筛选耗时长、效率低、药物筛选周期长等问题,提出一种基于2D模型的药物小分子筛选方法(SMS-2D)。利用计算机自动化筛选出与目标分子片段具有相似片段的药物小分子。实验结果表明:SMS-2D方法能高效地筛选出包含与分子片段具有相似片段的小分子。展开更多
Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation.The best compound 6 e with a sulfonyl scaffol...Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation.The best compound 6 e with a sulfonyl scaffold displayed EC(50)values of 0.0356μmol/L against WT and 0.0228μmol/L against HIV K103 N mutant strain.More pronounced,it had a lower cytotoxicity(CC(50)=99.6μmol/L),higher selectivity index(SIWT=2799,SIK103 N=4375)and better calculated logarithm of the octanol-water partition coefficient(cLogP)than the lead compound 3.Molecular docking and dynamics provided the binding modes of these compounds with reve rse transcriptase,explaining their activity.Collectively,the new compounds could be candidates for anti-HIV drug discovery.展开更多
基金the National Key R&D Program of China(2024YFA1306200)National Natural Science Foundation of China(22377119)+2 种基金Anhui Provincial Natural Science Foundation(2208085MC50)USTC Research Funds of the Double First-Class Initiative(YD9100002028,YD9100002036)Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM(QYPY20220008)for their financial support.
文摘Nuclear magnetic resonance(NMR)spectroscopy is an indispensable tool to probe weak protein-ligand interactions,which are key to the hit identification and hit-to-lead evolution in fragment-based drug discovery(FBDD).The integration of NMR technology in FBDD has facilitated the development of a diverse array of candidate compounds and FDAapproved drugs.Here,we summarized the rapid advancement and application of NMR techniques in contemporary China,which serves as a catalyst for the ongoing prosperousness of fragment-derived inhibitors against various targets.
基金National Natural Science Foundation of China(Grant No.21002002/21172012)
文摘Fragment-based drug discovery （FBDD） has been widely applied in the research of aspartyl protease inhibitors. In the present study, we reported our work on 2-aminobenzimidazole as the original fragment, which was predicted to bind with the catalytic aspartyl dyad （Asp228 and Asp32） of D-site amyloid precursor protein cleaving enzyme 1 （BACE1）. A series of novel 2-aminobenzimidazole derivatives were designed and synthesized. The results from FRET assay revealed that three out of the 12 designed 2-aminobenzimidazoles could inhibit more than 50% of the enzymatic potency of BACE1 at 10 pM. Docking study showed that 2-aminobenzimidazole could form multiple hydrogen bonds and occupy S1/$2＇ pockets well.
文摘基于片段的药物设计(Fragment-Based Drug Design,FBDD)是药物研发的主流方法之一。如何高效从海量药物大数据中筛选出具有相似分子片段的药物小分子成为生物化学研究领域的挑战性问题。针对目前人工筛选耗时长、效率低、药物筛选周期长等问题,提出一种基于2D模型的药物小分子筛选方法(SMS-2D)。利用计算机自动化筛选出与目标分子片段具有相似片段的药物小分子。实验结果表明:SMS-2D方法能高效地筛选出包含与分子片段具有相似片段的小分子。
基金financially supported by the National Natural Science Foundation of China(No.21372050)National Key R&D Program of China(No.2017YFA0506000)the Young Elite Scientists Sponsorship Program by the China Association for Science and Technology(No.2017QNRC061)。
文摘Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation.The best compound 6 e with a sulfonyl scaffold displayed EC(50)values of 0.0356μmol/L against WT and 0.0228μmol/L against HIV K103 N mutant strain.More pronounced,it had a lower cytotoxicity(CC(50)=99.6μmol/L),higher selectivity index(SIWT=2799,SIK103 N=4375)and better calculated logarithm of the octanol-water partition coefficient(cLogP)than the lead compound 3.Molecular docking and dynamics provided the binding modes of these compounds with reve rse transcriptase,explaining their activity.Collectively,the new compounds could be candidates for anti-HIV drug discovery.
